Abstract

Multiple members of the tumor necrosis factor superfamily (TNFSF) regulate the growth and branching of neural processes late in development when neurons are establishing and refining connections. Here we present the first evidence that a TNFSF member acts much earlier in development when axons are growing to their targets. CD40L transiently enhanced axon growth from embryonic mouse DRG neurons cultured at this early stage. Early spinal nerves of embryos lacking the CD40L receptor (Cd40−/− mice) were significantly shorter in vivo than those of Cd40+/+ littermates. CD40L was synthesized in early DRG targets and was co-expressed with CD40 in early DRG neurons. Whereas CD40L enhanced early axon growth independently of neurotrophins, disruption of a CD40L/CD40 autocrine loop impaired early neurotrophin-promoted axon growth. In marked contrast to the widespread regulation of axon and dendrite growth by CD40L reverse signaling later in development, CD40-Fc, which activates reverse signaling, had no effect on early sensory axon growth. These results suggest that CD40 forward signaling is a novel physiological regulator of early axon growth that acts by target-derived and autocrine mechanisms.

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